Overcoming tumor resistance mechanisms in CAR-NK cell therapy
Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.953849/full |
| _version_ | 1828518070825517056 |
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| author | Antonio Valeri Antonio Valeri Almudena García-Ortiz Almudena García-Ortiz Eva Castellano Eva Castellano Laura Córdoba Laura Córdoba Elena Maroto-Martín Elena Maroto-Martín Jessica Encinas Jessica Encinas Alejandra Leivas Alejandra Leivas Paula Río Joaquín Martínez-López Joaquín Martínez-López |
| author_facet | Antonio Valeri Antonio Valeri Almudena García-Ortiz Almudena García-Ortiz Eva Castellano Eva Castellano Laura Córdoba Laura Córdoba Elena Maroto-Martín Elena Maroto-Martín Jessica Encinas Jessica Encinas Alejandra Leivas Alejandra Leivas Paula Río Joaquín Martínez-López Joaquín Martínez-López |
| author_sort | Antonio Valeri |
| collection | DOAJ |
| description | Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent promising data in CAR-NK clinical trials point out the achievement of deep, high-quality responses, thus confirming its potential clinical use. Although CAR-NK cell therapy is not significantly affected by the loss or downregulation of its CAR tumor target, as in the case of CAR-T cell, a plethora of common additional tumor intrinsic or extrinsic mechanisms that could also disable NK cell function have been described. Therefore, considering lessons learned from CAR-T cell therapy, the emergence of CAR-NK cell therapy resistance can also be envisioned. In this review we highlight the processes that could be involved in its development, focusing on cytokine addiction and potential fratricide during manufacturing, poor tumor trafficking, exhaustion within the tumor microenvironment (TME), and NK cell short in vivo persistence on account of the limited expansion, replicative senescence, and rejection by patient’s immune system after lymphodepletion recovery. Finally, we outline new actively explored alternatives to overcome these resistance mechanisms, with a special emphasis on CRISPR/Cas9 mediated genetic engineering approaches, a promising platform to optimize CAR-NK cell function to eradicate refractory cancers. |
| first_indexed | 2024-12-11T18:50:10Z |
| format | Article |
| id | doaj.art-154ccf1c281141f49376a66fe85d08aa |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T18:50:10Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-154ccf1c281141f49376a66fe85d08aa2022-12-22T00:54:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-08-011310.3389/fimmu.2022.953849953849Overcoming tumor resistance mechanisms in CAR-NK cell therapyAntonio Valeri0Antonio Valeri1Almudena García-Ortiz2Almudena García-Ortiz3Eva Castellano4Eva Castellano5Laura Córdoba6Laura Córdoba7Elena Maroto-Martín8Elena Maroto-Martín9Jessica Encinas10Jessica Encinas11Alejandra Leivas12Alejandra Leivas13Paula Río14Joaquín Martínez-López15Joaquín Martínez-López16Hospital Universitario 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (H12O-CNIO) Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, SpainDepartment of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, SpainHospital Universitario 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (H12O-CNIO) Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, SpainDepartment of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, SpainHospital Universitario 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (H12O-CNIO) Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, SpainDepartment of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, SpainHospital Universitario 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (H12O-CNIO) Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, SpainDepartment of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, SpainHospital Universitario 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (H12O-CNIO) Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, SpainDepartment of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, SpainHospital Universitario 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (H12O-CNIO) Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, SpainDepartment of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, SpainHospital Universitario 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (H12O-CNIO) Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, SpainDepartment of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, SpainDivision of Hematopoietic Innovative Therapies, Biomedical Innovation Unit, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) and Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, SpainHospital Universitario 12 de Octubre-Centro Nacional de Investigaciones Oncológicas (H12O-CNIO) Haematological Malignancies Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, SpainDepartment of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, SpainDespite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent promising data in CAR-NK clinical trials point out the achievement of deep, high-quality responses, thus confirming its potential clinical use. Although CAR-NK cell therapy is not significantly affected by the loss or downregulation of its CAR tumor target, as in the case of CAR-T cell, a plethora of common additional tumor intrinsic or extrinsic mechanisms that could also disable NK cell function have been described. Therefore, considering lessons learned from CAR-T cell therapy, the emergence of CAR-NK cell therapy resistance can also be envisioned. In this review we highlight the processes that could be involved in its development, focusing on cytokine addiction and potential fratricide during manufacturing, poor tumor trafficking, exhaustion within the tumor microenvironment (TME), and NK cell short in vivo persistence on account of the limited expansion, replicative senescence, and rejection by patient’s immune system after lymphodepletion recovery. Finally, we outline new actively explored alternatives to overcome these resistance mechanisms, with a special emphasis on CRISPR/Cas9 mediated genetic engineering approaches, a promising platform to optimize CAR-NK cell function to eradicate refractory cancers.https://www.frontiersin.org/articles/10.3389/fimmu.2022.953849/fullchimeric antigen receptor (CAR)CAR NK cellshematologic tumorgenome editingCRISPR/Cas9tumor microenvironment |
| spellingShingle | Antonio Valeri Antonio Valeri Almudena García-Ortiz Almudena García-Ortiz Eva Castellano Eva Castellano Laura Córdoba Laura Córdoba Elena Maroto-Martín Elena Maroto-Martín Jessica Encinas Jessica Encinas Alejandra Leivas Alejandra Leivas Paula Río Joaquín Martínez-López Joaquín Martínez-López Overcoming tumor resistance mechanisms in CAR-NK cell therapy Frontiers in Immunology chimeric antigen receptor (CAR) CAR NK cells hematologic tumor genome editing CRISPR/Cas9 tumor microenvironment |
| title | Overcoming tumor resistance mechanisms in CAR-NK cell therapy |
| title_full | Overcoming tumor resistance mechanisms in CAR-NK cell therapy |
| title_fullStr | Overcoming tumor resistance mechanisms in CAR-NK cell therapy |
| title_full_unstemmed | Overcoming tumor resistance mechanisms in CAR-NK cell therapy |
| title_short | Overcoming tumor resistance mechanisms in CAR-NK cell therapy |
| title_sort | overcoming tumor resistance mechanisms in car nk cell therapy |
| topic | chimeric antigen receptor (CAR) CAR NK cells hematologic tumor genome editing CRISPR/Cas9 tumor microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.953849/full |
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